吴若豪 邱坤银 唐文婷 何展文

【摘要】目的 報道1例由COL6A1基因嵌合突变所致的Bethlem肌病，并分析该突变的致病性。方法 应用全外显子基因组测序法（trio-WES）对1例Bethlem肌病患儿及其父母进行基因测序，对检出突变进行生物信息学预测，并以“Bethlem肌病”“COL6A1”（包括中英文）为检索词在PubMed、CNKI、中华医学期刊全文数据库（MedBook）检索相关病例，在千人基因组数据库、ExAC数据库及ClinVar数据库检索患儿的基因突变。结果 经trio-WES检测发现，患儿COL6A1基因第8外显子存在1个c.868G > A （p.G290R）错义突变（突变频率为48.13%），该突变同时在其父亲外周血中检出，但突变频率仅7.89%，考虑为嵌合突变（突变频率<10%），属于新发突变（PS2）;该突变导致的蛋白水平改变发生在甘氨酸位置，属于COL6A1基因热点区域突变（PM1）;同时该突变在正常人群突变频率数据库中均不存在（PM2）。经多种有害突变预测软件预测结果均提示c.868G > A （p.G290R）为有害突变（PP2+PP3），根据美国医学遗传学与基因组学学会指南判定该新发错义突变为致病性突变（PS2+PM1+PM2+PP2+PP3）。在数据库检索到6例COL6A1基因突变所致Bethlem肌病先证者，无存在嵌合突变者。结论 COL6A1基因c.868G >

A （p.G290R）为该患儿罹患Bethlem肌病的致病原因，该突变未曾被报道，这在一定程度上扩充了COL6A1基因的变异谱。

【关键词】COL6A1基因;Bethlem肌病;嵌合突变;错义突变

Identification of a novel chimeric mutation in the COL6A1 gene of a child with Bethlem myopathy： a case report and literature review Wu Ruohao， Qiu Kunyin， Tang Wenting， He Zhanwen. Department of Pediatrics， Sun Yat-sen Memorial Hospital， Sun Yat-sen University， Guangzhou 510120，China

Corresponding author， He Zhanwen， E-mail：  hezhanw@mail.sysu.edu.cn

【Abstract】Objective To report one case of Bethlem myopathy caused by COL6A1 chimeric mutation and analyze the pathogenicity. Methods Trio-Whole Exome Sequencing （trio-WES） was conducted to detect the putative pathogenic mutations of the boy diagnosed with Bethlem myopathy and his parents. The impact of the detected mutations was predicted and validated by bioinformatics. Relevant cases were searched from PubMed， CNKI and MedBook databases using “Bethlem myopathy” and “COL6A1” as the keywords. The gene mutations of the affected child were searched from the mutation frequency databases of healthy population. Results A missense mutation of c.868G > A （p.G290R） in the exon 8 of COL6A1 gene was identified in the child and his father by trio-WES. However， the frequency of this mutation in his father was only 7.89%（<10%）， which was considered as chimeric mutation （de novo mutation） （PS2）. This mutation was glycine-related mutation， which was considered as hotspot variation in the COL6A1 gene （PM1）. However， this mutation was absent in major allele frequency databases （PM2）. The results of multiple pathogenic variant prediction software prompt that c.868G > A （p.G290R） is a pathogenic mutation （PP2+PP3）. According to the American College of Medical Genetics and Genomics （ACMG） variant classification guidelines， the variant of c.868G > A （p.G290R） in the COL6A1 gene in this child was classified as pathogenic mutation （PS2+PM1+PM2+PP2+PP3）. After literature review， six probands of Bethlem myopathy with COL6A1 variant were searched. However， Bethlem myopathy with COL6A1 chimeric variant has not been reported. Conclusion The chimeric mutation of c.868G > A （p.G290R） in the COL6A1 gene is the pathogenesis of Bethlem myopathy， which has not been reported. This case report expands the variation spectrum of COL6A1 gene.

【Key words】COL6A1 gene;  Bethlem myopathy;  Chimeric mutation;Missense mutation

Bethlem肌病（BM）是一种常染色体显性遗传性肌病，由COL6A1基因变异所致。2011年，Bönnemann[1]阐明该先天性疾病的临床表现主要为近端肌无力、长手指屈肌、手肘及脚踝等关节挛缩。该病发病年龄不定，产前期可仅表现为胎儿运动减少;新生儿期可出现四肢肌张力减弱或斜颈;婴幼儿期可出现运动发育迟滞、肌无力及关节挛缩;成年期多有较为明显的近端肌无力及跟腱、长指屈肌挛缩。……